U.S. patent application number 13/444279 was filed with the patent office on 2012-10-18 for use of d-ribose for fatigued subjects.
This patent application is currently assigned to Bioenergy, Inc.. Invention is credited to Dean J. MacCarter, John A. St. Cyr.
Application Number | 20120264701 13/444279 |
Document ID | / |
Family ID | 41172394 |
Filed Date | 2012-10-18 |
United States Patent
Application |
20120264701 |
Kind Code |
A1 |
St. Cyr; John A. ; et
al. |
October 18, 2012 |
USE OF D-RIBOSE FOR FATIGUED SUBJECTS
Abstract
Low doses of D-ribose raise the level of fitness and lower the
perception of fatigue in baby boomers aged 45-65 who perceive
themselves as fatigued. The doses range from 0.100 grams to 3.0
grams, bid, for a total of 0.200 to 6.0 grams daily. Objective
measures of cardiopulmonary parameters confirm the improvement of
fitness and questionnaires confirm that quality of life and mental
states are improved with D-ribose administration.
Inventors: |
St. Cyr; John A.; (Coon
Rapids, MN) ; MacCarter; Dean J.; (Englewood,
CO) |
Assignee: |
Bioenergy, Inc.
Ham Lake
MN
|
Family ID: |
41172394 |
Appl. No.: |
13/444279 |
Filed: |
April 11, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12583430 |
Aug 20, 2009 |
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13444279 |
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61189498 |
Aug 20, 2008 |
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61208122 |
Feb 20, 2009 |
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Current U.S.
Class: |
514/23 |
Current CPC
Class: |
A61P 1/14 20180101; A61K
9/0056 20130101; A61K 9/08 20130101; A61P 3/00 20180101; A61K 9/20
20130101; A61P 9/00 20180101; A61P 25/00 20180101; A61P 11/00
20180101; A61P 3/02 20180101; A61K 31/7004 20130101 |
Class at
Publication: |
514/23 |
International
Class: |
A61K 31/7004 20060101
A61K031/7004; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method comprising the oral administration of an effective
amount of D-ribose to aging subjects experiencing fatigue wherein
the symptoms of fatigue are relieved.
2. The method of claim 1 wherein the effective amount of D-ribose
is 0.1 to 3 grams administered at least twice a day.
3. The method of claim 1 wherein the effective amount of D-ribose
is 0.2 to 6 grams per day.
4. The method of claim 1 wherein the symptoms of fatigue comprise
tiredness, drowsiness, lethargy, malaise, and/or weakness.
5. The method of claim 1 wherein the effective amount of D-ribose
is administered as a single product or in combination with other
dietary supplements, pharmaceuticals or food.
6. The method of claim 5 wherein the effective amount of D-ribose
is incorporated in a lozenge, tablet or time-release tablet or
dissolved in water.
7. The method of claim 1 wherein the effective amount of D-ribose
is sprinkled on food.
8. A method comprising the oral administration of an effective
amount of D-ribose to aging subjects experiencing a reduced quality
of life, wherein the symptoms of a reduced quality of life are
relieved.
9. The method of claim 8 wherein the effective amount of D-ribose
is 0.1 to 3 grams administered at least twice a day.
10. The method of claim 8 wherein the effective amount of D-ribose
is 1 to 6 grams per day.
11. The method of claim 8 wherein the reduced quality of life
includes lowered vitality, social functioning, emotional wellbeing,
and/or mental competence.
12. A method for relieving the symptoms of fatigue comprising the
administration of 0.2 to 6 grams per day of D-ribose to a healthy,
aging subject experiencing fatigue, wherein the symptoms of fatigue
are relieved.
13. The method of claim 12 wherein 0.2 to 3 grams per day D-ribose
is administered to the healthy, aging subject.
14. A method for relieving the symptoms of fatigue comprising the
administration of 0.2 to 6 grams per day of D-ribose to an aging
subject experiencing fatigue, wherein the aging subject does not
have cardiovascular disorders, pulmonary disorders, and/or
metabolic disorders; wherein the fatigue is not due to increased
energy expenditure from exercise or physical labor; and wherein the
symptoms of fatigue are relieved.
15. The method of claim 14 wherein 0.2 to 3 grams per day D-ribose
is administered to the aging subject.
16. The method of claim 14 wherein the aging subject is
healthy.
17. The method of claim 16 wherein 0.2 to 3 grams per day D-ribose
is administered to the healthy, aging subject.
Description
RELATED APPLICATIONS
[0001] This is a continuation of application U.S. Ser. No.
12/583,430, filed Aug. 20, 2009, which claims the benefit of U.S.
Provisional Applications Ser. Nos. 61/189,498, filed Aug. 20, 2008,
and 61/208,122, filed Feb. 20, 2009, all of which are herein
incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] Over the last twenty years, many studies have shown the
benefit of oral or intravenous administration of D-ribose, a
naturally occurring pentose carbohydrate, to restore, energy levels
in persons in whom ATP levels are low due to cardiac ischemia,
congestive heart failure, poor pulmonary function and other such
conditions. Healthy persons undergoing increased demand for energy
such as those exercising intensely, have also benefitted from
D-ribose supplementation.
[0003] The energy coinage of the cell is adenosine triphosphate
(ATP). During anabolism, the energy derived from the metabolism of
nutrients is transferred to high energy phosphate bonds of ATP. The
energy in these bonds is expended during the energy consumption
phase. During energy consumption, ATP loses one high energy bond to
form ADP, which can be hydrolyzed to AMP. AMP and its metabolites
adenine, hypoxanthine, xanthine and inosine are freely diffusible
from the muscle cell and may not be available for resynthesis to
ATP via the salvage pathway. The energy buildup steps occur within
the cell during two basic processes. Oxidative phosphorylation
replenishes ATP by the breakdown and phosphorylation of circulating
fatty acids, glucose and intramuscular glycogen and triglycerides,
through the Krebs tricarboxylic acid cycle, with oxygen as a
terminal electron acceptor. Anaerobic phosphorylation provides ATP
via the Emden-Meyerhoff pathway of glycolysis derived from
circulating glucose and intramuscular glycogen via kinase reactions
such as the myokinase reaction. Lactic acid is the final product of
anaerobic glycolysis.
[0004] Regardless of whether the high energy phosphate bonds of MP
are generated oxidatively or anaerobically, and irrespective of the
substrates used for its generation, ATP cannot be synthesized
unless the precursors of the ATP molecule itself are available. The
resynthesis of the ATP molecule can occur by either de novo or
salvage pathways. Synthesis by the de novo pathway is slow. Ribose
is found in the normal diet only in very low amounts, and is
synthesized from glucose within the body by the pentose phosphate
pathway. In the de novo synthetic pathway, ribose is phosphorylated
to 5-phosphoribosyl-1-phosphate pyrophosphate (PRPP), and condensed
with adenine to form the intermediate adenosine monophosphate
(AMP). AMP is further phosphorylated via high energy bonds to form
adenosine diphosphate (ADP) and ATP. Normally, AMP synthesis is
believed to occur mainly by the salvage pathway, however, following
anoxia or ischemia where breakdown products diffuse from the cells,
the activity of the de novo pathway is increased.
[0005] In the synthesis of ATP via the nucleotide salvage pathway,
the nucleotide precursors that may be present in the tissue are
converted to AMP and further phosphorylated to ATP. Adenosine is
directly phosphorylated to AMP, while the breakdown products
xanthine and inosine are first ribosylated by PRPP and then
converted to AMP. AMP is further phosphorylated via high energy
bonds to form adenosine diphosphate (ADP) and ATP.
[0006] ATP is necessary for all bodily functions, such as muscle
contraction, brain function, digestion and others. A lack of ATP
can result in feelings of fatigue, lowered mental capacity, lack of
"get up and go" and a lessened quality of life. Barring illness or
disease, most persons who are adequately nourished experience
fatigue only during extended or extreme exercise. Fatigued subjects
without known cardiovascular, pulmonary or metabolic disorders
would be assumed to have adequate ATP levels for normal function.
"Baby Boomers" are defined as those persons born between 1946-1964
and are now approximately 80 million in number. Approximately 20%
of Americans in this population complain of fatigue, which can
interfere with their daily, normal life style, especially when many
have achieved success in their profession, with the increased
demands that success requires. The perception of fatigue is vague,
encompassing symptoms such as tiredness, drowsiness, lethargy,
malaise, weakness or a lack of energy. Many baby boomers try to
regain a more energetic state in order to continue their careers at
a high level and to make their future true "golden years" with a
high quality of life. There is no theoretical basis for assuming
that older, healthy but sedentary persons such as baby boomers, now
aging, would benefit from dietary supplementation.
SUMMARY OF THE INVENTION
[0007] Fatigued, aging subjects without known cardiovascular,
pulmonary or metabolic disorders or known increased energy
expenditure due to exercise or physical labor, were administered
1.5 or 3.0 grams of D-ribose orally twice a day (bid) for two
weeks. Those subjects at the higher dose of six grams of D-ribose
per day showed significant improvement in cardiovascular
parameters; that is, had improved levels of fitness as assessed by
a decrease in cardiac work on on moderate exercise, improved
aerobic capacity, breathing efficiency and O.sub.2 uptake
efficiency. Their self perceived levels of fatigue decreased by an
average of 50%.
[0008] Subjects at the 1.5 grain dose bid or 3.0 grams of D-ribose
a day showed less improvement at two weeks, but when administration
was continued for an additional two weeks, positive trends were
found in both objective and subjective assessments.
[0009] D-ribose, a white powder, was administered in a small amount
of water, but can be incorporated in a lozenge, tablet or time
release tablet or sprinkled on food. In addition to being
administered as a single product, D-ribose may also be administered
in combination with other dietary supplements, pharmaceuticals,
foods or drinks.
[0010] Since the levels of improvements in the parameters measured
increased from week one to week two and to week four in the lower
dose subjects, it is indicated that improvement would increase and
the D-ribose supplement should be administered chronically or long
term. Both the number and amount of the dose and the total amount
of D-ribose to be ingested each day are important. Each dose may be
from 0.100 gram to 3.0 gram repeated at least twice a day. If lower
doses are given, the daily total of D-ribose ingested should be
from 1.0 to 6.0 grams.
DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows a typical example of the detection of anaerobic
threshold.
[0012] FIG. 2 shows the anaerobic threshold shift after two weeks
of oral D-ribose.
[0013] FIG. 3 shows the heart rate to METS ratio at the anaerobic
threshold.
[0014] FIG. 4 shows the net energy expenditure at the anaerobic
threshold.
[0015] FIG. 5 graphically displays a summary of SF-36
questionnaire.
[0016] FIG. 6 displays a summary of the fatigue questionnaire.
[0017] FIG. 7 shows a trend in reducing fatigue.
DETAILED DESCRIPTION OF THE INVENTION
[0018] Many individuals, as they age, slow down, exercise less, eat
the same amount of food and gain weight. This cycle feeds on itself
and can result in health problems such as heart disease and
diabetes. At the end of the work day, which is for many persons a
sedentary work, few actively pursue exercise on a regular basis
with many complaining of fatigue and tiredness with limited energy
and little desire or motivation for exercise. Theoretically, these
individuals are probably de-conditioned with undesirable basic
metabolism index (BMI) values and "down-regulated" pathways for
energy production, feeding into the cycle and perpetuating their
inactivity. These negative effects of aging in baby boomers over 45
years of age, occur at a time when the subject has achieved
professional success and would like to find a natural means,
without side effects, for increasing energy and quality of life.
The following study was designed to test whether supplementation
with D-ribose can aid in breaking the sedentary cycle so as to
improve the fatigue state and even to encourage more physical
activity with all its concomitant benefits.
[0019] The pilot study focused on older healthy adult aged over 45
years to 65 years. Although the subjects enrolled were 65 or less,
the supplementation is recommended for any older adult over 45 up
to and including advanced old age.
Example 1
Selection of Subjects and Assessment
[0020] The pilot study was performed enrolling 20 aging subjects,
greater than 45 years of age, who were self-perceived as fatigued
and tired as their customary daily state for at least one month,
with no strenuous exercise or physical labor to account for the
fatigue. No subjects had documented histories of heart/lung or
metabolism/endocrine disease, as set out more fully below in the
inclusion criteria. The causes of fatigue in aging subjects is
unknown. It can be hypothesized that the causes are mental, since
lowered cognition and feeling of well being is also common in aging
persons. The aforementioned studies of unhealthy persons or persons
exercising strenuously found a dose of five to eight grams of
D-ribose, taken two to four times per day was recommended to raise
or maintain ATP levels. Lower amounts such as in this study, were
not found adequate for those subjects. For the healthy, but
sedentary and aging subjects for this study, it was expected that
they were already at an optimum ATP level. Two doses of oral
D-ribose at 1.5 grams or 3.0 grams bid were selected to test the
hypothesis that raising ATP levels with D-ribose could have some
benefit in improving fatigue. Each subject consumed the oral
D-ribose for two weeks, dissolved in a small amount of water. Study
assessments were done at baseline, and at one and two weeks during
the trial. The lower dose study was continued an additional two
weeks. The subjective and objective assessment parameters included:
sub-maximal exercise performance, resting and sub-maximal energy
expenditure, the SF-36 Quality of Life Assessment and a subjective
questionnaire for evaluating fatigue.
A. Inclusion Criteria.
[0021] Subjects of either gender, between the ages of 45 and 65
years of age, who have had no previous clinical diagnosis of
pulmonary, cardiac or metabolic disorders, were eligible to be
included in the study. The subjects must have been capable of
performing a sub-maximal incremental treadmill exercise using
cardiopulmonary analysis methods. Mild, untreated per-hypertension
(>120/70 but <140/90) was acceptable. Subjects agreed to be
compliant with the dose regimen, repeat clinical visits and
completion of the study questionnaires. Subjects should not have
been taking other adenine nucleotide enhancing supplements such as
creatine, carnitine or the like for at least a month before
entering the study and during the period of the study.
Non-compliance in previous studies or pregnancy were further
exclusion criteria.
B. Assessment.
[0022] Subjects were monitored at baseline and during the two week
treatment period for their perceived fatigue activity levels.
Subjects were asked to rate on a ten point scale (1=near dead to
10=excellent) the following questions: How is your energy? (1=no
energy, 10=excellent); How do you sleep? (1=no sleep, 10=8 hours
without waking); How is your mental clarity? (1="brain fog",
10=good clarity); How bad is your pain?; How is your overall sense
of well being? At weeks one and two, subjects were also asked to
describe their overall rating of symptoms of fatigue as compared to
their symptoms at baseline. The five point scale was; much better,
somewhat better; no change; somewhat worse and much worse. The
investigators selected end-points of some assessments to determine
whether the subjects remained the same or improved at one and two
weeks. The results were represented in a Visual Analog Scale (VAS)
for fatigue.
[0023] The SF-36 Quality of Life Questionnaire was also used.
Subjects were asked to fill out a questionnaire on the normal
activities that they participated in. These activities included
household chores, walking, yard work and whether the subject
routinely climbed stairs. Additionally, subjects were asked how
many days in the past week they felt good; missed work or routine
chores because of fatigue; how tired they felt and their state on
awakening in the morning.
C. Cardiopulmonary Exercise Testing.
[0024] Energy expenditure was calculated both at rest (BMR) and
also at the anaerobic threshold (AT) using standard formulae
incorporated into CPX-based software. Net energy expenditure was
determined by subtracting resting values from those calculated at
the subject's AT. In addition, the completed activity log was used
to determine potential changes in cumulative (daily and weekly)
energy expenditure throughout the first and second weeks while on
D-ribose. Further, work efficiency was determined by calculating
the reciprocal of aerobic power or the VO.sub.2 to WR ratio, as
computed at the anaerobic threshold. FIG. 1 shows an example of the
exercise program and the AT point.
[0025] The formula for calculation of energy expenditure at the
anaerobic threshold was based, in part, on the actual measured
resting energy expenditure (RER) and VO.sub.2 at that level of
exercise, knowing that a subject can sustain a steady state at the
initial phase of the AT, which represents a particular phase of
exercise whereby energy metabolism due to an increase in oxygen
consumption resulting in a reduction in tissue oxygen perfusion
shifts to an anaerobic instead of an oxidative phosphorylation. The
AT interval varies from person to person depending on physical
condition or training. Individuals who are not trained and
relatively deconditioned have a low AT, as compared to elite
endurance athletes having a high AT. At the AT, fuel mix for
skeletal muscle metabolism is somewhat balanced. This point occurs
in the range between 40% to 60% of the maximum VO.sub.2 attained.
For example, assuming that equal amounts of fats and carbohydrates
are oxidized at an RER of 0.85 just prior to AT onset, energy
expenditure can be calculated using the formula
VO.sub.2(L/min).times.4.862 kcal/min for each liter of oxygen
consumed. Likewise, if an individual was at an RER of 0.89 under
steady state conditions, their absolute VO.sub.2 in L/min would be
multiplied by a factor of 4.911. Net energy expenditure would be
calculated subtracting the subject's resting energy expenditure
(REE) or BMR. METS or net metabolic equivalents was also used to
express the subject's activity level at their AT.
D. Sub-Maximal Treadmill Exercise Protocol.
[0026] For this study, a ramping incremental treadmill exercise
protocol was followed. Treadmill speed was incrementally increased
by 0.3 mph every minute and grade was increased by 2% each minute,
until the patient scores his or her level of exertion to be greater
than 14 on the Borg 6-20 scale. The treadmill exercise was
increased from 0 mph to 3.0 mph and the elevation increased from 0
to 12%, over the test time of six minutes. The Borg perceived
exertion index scale goes from 7 (very, very light) to 13 (somewhat
hard) to 19 (very, very hard). No patient was asked to exercise
past 14 on the Borg scale. The exercise was stopped at that point
and time to reach a Borg scale of 14 was noted.
[0027] A more detailed explanation of the various parameters
assessed in this application is available in U.S. patent
application Ser. No. 11/118,613, the teachings of which are hereby
incorporated by reference.
Example 2
Pilot Study
[0028] A study was performed to test the proposed assessment
protocol. Twenty subjects were given 1.5 grams or 3.0 grams of
D-ribose bid orally for two weeks. The following results showed the
increase or decrease in the parameters measured at the end of the
two weeks in those subjects receiving 3.0 grams of D-ribose bid or
six grams total per day.
1) Net energy expenditure at the AT onset rose by 32%, with
p<0.0005. 2) Resting energy expenditure at the AT onset
increased by 8.2%. 3) VO.sub.2 at the AT onset increased by 18%,
with p<0.001. 4) Heart rate at the AT onset increased by 9.2%,
with p=0.012. FIG. 2 shows the shift in AT onset after two weeks of
D-ribose supplementation and the improvement in parameters. Table 1
summarizes the changes in parameters.
TABLE-US-00001 TABLE I Sub Maximal CPX Testing Visit Mean change P
value VO.sub.2 at AT Week 1 1.53 +/- 0.90 0.0005 Week 2 2.13 +/-
0.78 <0.0001 VE Slope Week 1 -2.26 +/- 1.69 0.0022 Week 2 -2.44
+/- 2.24 0.0074 O.sub.2 Uptake Slope Week 1 0.17 +/- 0.19 0.0215
Week 2 0.24 +/- 0.15 0.0008 HR to METS ratio Week 1 -3.00 +/- 2.83
0.0085 at AT Week 2 -3.67 +/- 3.27 0.0063 Net Energy Week 1 9.32
+/- 7.67 0.0040 Expenditure at AT Week 2 16.23 +/- 6.13
<0.0001
[0029] These results indicate that energy efficiency was improved,
even over this short term. The average calorie burned from fat
substrate at the AT did not change significantly in most subjects,
although five subjects showed an actual increase in fat burn
calories.
[0030] The heart rate to METS ratio decreased by 11.7%, while the
ventilatory efficiency slope decreased by 8.5%. The oxygen pulse
indexed to inspiratory drive decreased by 8.9%, which possibly
indicated less cardiac stroke work. The change in oxygen pulse
times the change in expired CO.sub.2 at AT increased by 60.8%,
which may be a significant measure of improved efficiency. FIG. 3
is a graphic display of these results, showing the lowered heart
rate to METS ratio at AT, indicating that the heart does not have
to work as hard at AT to perform as much work. This measure of
energy utilization at the cellular level is reflective of an
improvement in level of fitness. FIG. 4 again shows net energy
expenditure at AT, which is a measure of work performed. Thus, the
body is more efficient at energy utilization following two weeks of
D-ribose supplementation.
FIG. 5 shows the analyzed results of the SF-36 questionnaire The
baseline questionnaires indicated a frequent occurrence of reduced
quality of life. The most significant improvement in symptoms was
in "vitality," while the increases in social functionality,
emotional wellbeing, mental health and mental competence were
unexpected and had not been seen in previous studies with subjects
having cardiovascular disease or healthy subjects exercising past
moderate exercise.
[0031] Nine subjects completed the VAS forms of subjective estimate
of tiredness. On a scale of 0 (no fatigue) to 10 (very tired), the
average score was 47 at baseline and 20 at two weeks. Several
observations were of interest: one subject reported an improvement
from 80 to 20; another remained at an estimate 50; while those with
low initial estimates did not change. FIG. 6 summarizes those
results with the composite scores of all participants displayed in
a bar graph.
[0032] Subjects receiving the lower dose of D-ribose showed
positive trends in several parameters. The fatigue questionnaire at
two weeks showed a slight reduction in fatigue, although not as
significant as that for the higher dose of D-ribose. Therefore,
D-ribose administration was continued for an additional two weeks.
Continued improvement was found, as shown in FIG. 7. The response
to the SF-36 questionnaire showed improvement in symptoms of
general health, vitality and mental outlook at four weeks. The
objective measures showed less compelling results; there was
definitely a positive trend in CPX parameters that increased from
two weeks to four weeks. Based on these results it is expected that
even lower doses, as low as 0.100 grams, can relieve the symptoms
of fatigue in these subjects, provided that the daily total is 1.0
to 6.0 grams of D-ribose. For example, if a subject ingests a dose
of 0.100 grams, the subject would take 10 doses a day in order to
benefit from the supplementation.
[0033] D-ribose ingestion is known to have the potential to cause
gastrointestinal distress, including flatulence and diarrhea, and
also can lower blood glucose. No subjects in this study, at either
the higher or the lower doses, experienced any side effects of
D-ribose administration.
[0034] In summary, D-ribose administration to aging, healthy but
sedentary baby boomers over the age of 45 years, improved subjects
vitality and enhanced their quality of life. Surprisingly, subjects
reported improvement in mental functions.
* * * * *